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Friday, November 14, 2014

Injection Site Reactions and Liver Toxicity Emerge as Major Issues for GalNAc-siRNA Technology

Alnylam this morning reported top-line results from a phase
II study of their first clinical candidate based on the GalNAc-siRNA conjugate
delivery technology, ALN-TTRsc for TTR amyloidosis. Accordingly,
average knockdowns of ~85% were seen in the 5mg/kg dose group, thus confirming
the robust potency at around the dose that the company plans to take forward in
later-stage studies.

Such potency, however, came
at the apparent expense of relatively frequent injection site reactions (23% of patients), with an additional skin reaction seen outside the area of injection. Moreover, there was a trend towards elevated liver enzymes, a marker of liver toxicity, including one that was adjudicated a serious adverse event (SAE;
~4x ULN deemed mild severity).

The efficacy data do not come as a surprise given that they
were largely in line with that seen in the phase I study a year ago, which
included the same dose group (5mg/kg) at the same dosing schedule (first 5x
daily, then weekly for 5 weeks). In both
cases average TTR reductions of ~85% were seen, with the difference being that this study involved
23 subjects at this dose (plus 3 subjects at 7.5mg/kg which was not further pursued for undisclosed reasons) while the phase I study involved only 3 comparable subjects.

The efficacy is thus in line with the intravenous ALN-TTR02
which utilizes Tekmira’s liposomal delivery technology and which so far has
been very well tolerated. Critics (aka LNP haters), however, are keen to point out the
use of (transient) immune suppression.
The efficacy of ALN-TTRsc is superior to the antisense compound by ISIS and GSK which
has shown 70% target gene knockdown in a short 4-week phase I study. Assuming maximal knockdown efficacy has not
been reached at this time-point, ISIS-TTRRx is likely to max out between 75 and
80%.

Similar to potency, the injection site reactions were not really a surprise given that in the phase I study this was the most common side
effect. What is new is that there was a
skin reaction that occurred outside the area of injection possibly indicating
systemic immune activation.

The liver enzyme elevations, however, were certainly
new. This could be related to histologic observations of granulations in the cytoplasm of hepatocytes, likely reflecting
storage sites of the fairly stable modified RNAi triggers.

My hope and expectation is that particularly the injection site reactions, but also liver enzyme elevations will
lessen with the lower doses enabled by the more effective second generation ESC GalNAc chemistry. Still, for ALN-TTRsc the safety
profile looks adequate for an indication like FAC (familial amyloidotic
cardiomyopathy), but 23 is still a small number to be sure.

Lastly, if I had to choose between
ALN-TTRsc, ISIS-TTRRx, and ALN-TTR02, I would go with ALN-TTR02 with the best
apparent risk:reward, regardless of whether it's an intravenous procedure or not.

Disclosure: Long ISIS Pharmaceuticals, no positions in Tekmira and Alnylam.

You got it right, RG-101 will not involve a demanding dosing schedule as ALN-TTRsc. Having said that, I expect that if AEs emerge for RG-101, it will be along the lines of ALN-TTRsc though milder in severity, and keep in mind, RG-101 is not a chronic therapy. My expectation is 2 doses max spaced 1 month apart.

Dirk, You've integrated disparate contradictory new knowledge into your analysis, once again. I'm impressed. In my humble opinion you now have a 25% rating vis a vis McCamant. You've done so well in this field I would be foolish to offer you advice, and so I'll only offer an old general adage that I have found to be true: The first million is the hardest to make. Best Wishes.

Considering Arcturus is getting comparable knock down at 0.3 mg/kg, has shown no DLTs up to 50 mg/kg, and is talking about once a month treatments v multiple injections with painful reactions on a weekly basis... I would expect that the TTR market is heading into a major shake up.

If the ALNY GalNac-sirna delivery is so adverse then the downstream effect for RGLS can't be great one would assume.

Yet it is RGLS which was able to raise the needed capital and fully enrol for its upcoming trials. Which kind of negates any concerns an investor would have because of the regulatory approval required to get to that point.

Which brings us back to the question of why does Benitec have such a stringent control on its trial? The upshot being only two patients have been dosed. The second conveniently on the eve of the annual meeting.

My conclusion; it is because of serious toxicity concerns from the FDA.

It's much more likely that the stringent protocol is about the irreversibility of the Benitec ddRNAi infusion. Off target effects being the risk. NHPs recieved excessive amounts of TT-034 without toxicity.

What is all this fuss about AE? All the AE were transient and returned to baseline level while the dosing continued. TTRsc continues to move into P3. It is not like TKMR-EBOLA which was halted by FDA. Issue with TTRsc is not AE or potency but clinical end points. There is a hotchpotch of a number of clinical end points to measure the clinical efficacy of TTRsc. This will make it more complicated to measure the clinical efficacy in FAC patients.

Second patient dosed, future patients much easier to source, toxicity issues are a feint and not a hint of FDA issue with toxicity. Fact is the protocol is rightly stringent, this is ddRNAi not siRNAi or antisense. In other words it is the real deal and NHP extensive toxicity testing points to safety not being an issue and efficacy hinted by 2nd cohort. How long can you afford to sit out the most promising and exciting RNAi platform that is soon to show validation. You liked RGLS 150% one day gain? Prepare for 150-300% when 3rd patient data flows and/or Calimune reports. Good luck all Benitec shorts or sideline sitters, you're going to need it. Keep sitting on TKMR and RGDO and kiss your cash goodbye.

Some other self storage companies benefit from people who are unable to pay the rent for their storage unit by having auctions to sell their possessions. But this team at Storage in Croydon is very nice, professional, and helpful.

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